Pancreatic carcinoma patients face almost certain death at the time their cancer is diagnosed because of the high incidence of invasion and metastasis associated with this disease. Perineural invasion is a common and prominent feature of pancreatic cancer that actively contributes to patient mortality by complicating curative tumor resection through widespread dissemination and early metastasis. Our understanding of perineural invasion is poor. If we are to develop more effective treatments for pancreatic cancer patients, we must better understand and learn to control perineural invasion. Toward this goal, we study integrins, which are receptors for the extracellular matrix that transduce signals that are critical for tumor invasion. In our preliminary data, we have identified two integrin species, alpha6beta4 and alpha4beta7, that show a good correlation with the increased aggressiveness of pancreatic carcinoma. However, how these integrins contribute to perineural invasion is largely unknown. The long-term goal of this project is to elucidate the overall mechanism of pancreatic carcinoma cell invasion of the peripheral nerves. The objective of this proposal is to understand how pancreatic carcinoma cell integrins contribute to invasion along perineural spaces. Our first aim is to define the role of the alpha6beta4 integrin, which has been shown to promote invasion other carcinoma systems, in the invasive phenotype of pancreatic carcinomas. Our next aim is to determine the functional significance of the proinflammatory integrin alpha4beta7 in pancreatic carcinoma perineural invasion. This aim is based on our unique preliminary observation that the alpha4beta7 integrin can be expressed on pancreatic carcinoma cells and may help to more fully explain how inflammation in pancreatic carcinoma progression. For these studies, we will use three-pronged approach, which includes: in vitro studies with human pancreatic carcinoma cell lines that have been characterized for their integrin content; assessment of resected tumor tissue for the alpha4beta7 and alpha6beta4 integrins and their respective ligands; and a transgenic mouse model of pancreatic carcinoma. Each of these approaches is chosen to utilize the strengths of each system so that we may better understand perineural invasion of pancreatic carcinoma and identify targets for therapeutic intervention.